Calreticulin Mutant–Induced MHC-I Skewing Supports Heteroclitic Peptide Vaccine Use

Myeloproliferative neoplasms (MPN) that lack the common JAK^V617F typically exhibit an insertion or deletion frameshift mutation in calreticulin (CALR^MUT) that promotes oncogenesis. Due to their prevalence and tumor-promoting abilities, these calreticulin mutations have served as targets for neoantigen-based cancer vaccines, but studies have demonstrated limited immunogenicity and a lack of CALR-specific T cells. Gigoux and colleagues sought to examine the mechanisms that underlie this lack of CALR-specific T cells, finding that, in a large cohort of patients, major histocompatibility complex class I (MHC-I) alleles that were predicted to strongly bind to CALR^MUT peptides were less prevalent in patients with CALR^MUT MPN, while alleles that demonstrate poor predicted binding were overrepresented, indicating that selective immune pressure promotes this MHC-I allele skewing. Testing using peripheral blood mononuclear cells from healthy donors positive for underrepresented MHC-I alleles revealed induction of an immune response against CALR^MUT peptides, suggesting that individuals with MHC-I alleles that efficiently present CALR^MUT peptides are potentially less likely to develop CALR^MUT MPN. Additional investigation into approaches to induce an immune response against patients with CALR^MUT MHC-I skewing showed that use of an anchor-optimized heteroclitic peptide vaccine targeting the CALR^MUT peptide starting at position 2 (CALR9p2) increases cross-reactive CALR^MUT-specific CD8⁺ T-cell activation better than a vaccine composed of the nonmodified CALR9p2 peptide. Furthermore, this MHC-I skewing was modeled in C57BL/6J mice and use of the CALR9p2 heteroclitic variant with the strongest predicted affinity [CALR9p2(T5F)] in these mice induced a cross-reactive CALR9p2 immune response. Moreover, increased tumor cell killing and improved survival were observed as compared to adjuvant alone, and addition of immune checkpoint blockade through use of an anti–PD-1 antibody further increased these effects. In summary, this study reveals that negative MHC-I skewing in patients with CALR^MUT MPN is due to immune-mediated rejection and use of a heteroclitic peptide vaccine in this patient population could serve as a therapeutic option.

Gigoux M, Holmstöm MO, Zappasodi R, Park JJ, Pourpe S, Bozkus CC, et al. Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine. Sci Transl Med 2022;14:eaba4380.

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